ES2609595T3 - Manufacture of 2- (5-Bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthium) acetic acid - Google Patents

Abstract

A process for preparing a compound of Formula (III): ** Formula ** comprising contacting a compound of Formula (II): ** Formula ** where R is -C1-C20 alkyl, -C1-alkenyl- C20, -C3-C10-cycloalkyl or -C3-C10 -cycloalkenyl; with N-bromosuccinimide (NBS) and a solvent.

Description

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DESCRIPTION

Manufacture of acid 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthium) acetic Background of the invention

Uric acid is the result of xanthine oxidation. Uric acid metabolism disorders include, but are not limited to, polycythemia, myeloid metaplasia, gout, a recurrent gout attack, gouty arthritis, hyperuricemia, hypertension, cardiovascular disease, coronary heart disease, Lesch-Nyhan smdrome, Kelley smdrome - Seegmiller, kidney disease, kidney stones, kidney failure, inflammation of the joints, arthritis, urolithiasis, plumbism, hyperparathyroidism, psoriasis or sarcoidosis.

Summary of the invention

In a first embodiment, the present invention provides a process for preparing a compound of Formula (III):

image 1

which comprises contacting a compound of Formula (II):

image2

wherein R is -C1-C20 alkyl, -C1-C20 alkenyl, -C3-C10-cycloalkyl or -C3-C10-cycloalkenyl; with N-bromosuccinimide (NBS) and a solvent.

Effective synthetic procedures are often required for large-scale pilot plant synthesis of chemical compounds. Certain scalable methods and methods for the synthesis of compounds of Formula (I) are described herein:

image3

in which

R is H, -C1-C20 alkyl, -C1-C20 alkenyl, -C3-C10 cycloalkyl, -C3-C10 cycloalkenyl or R is a conjugated ion; and

Y is H, OH, NH2, F, Cl, Br or I.

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The compounds of Formula (I) described herein are useful for the treatment of disorders of uric acid metabolism.

In one aspect, a procedure (Procedure 1) for preparing:

image4

image5

(Compound 1) or (Compound 4)

which comprises contacting a compound of Formula (II) or a salt thereof,

image6

wherein R is -C1-C20 alkyl, -C1-C20 alkenyl, -C3-C10 cycloalkyl or C3-C10-cycloalkenyl, with N-bromosuccinimide (NBS) and a solvent to provide a compound of structure:

image7

Formula (III)

In some embodiments of the process described above, R is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, isoamyl, pentyl, hexyl, heptyl, octyl, nonyl, terpenyl, bornyl, allyl, linalyl or geranyl.

In certain embodiments of the process described above, R is methyl or ethyl. In some specific embodiments of the process described above, R is methyl.

In some embodiments of the process described above, the reaction mixture is stirred for at least 12 hours at a temperature between room temperature and 32 ° C.

In some embodiments of the procedure described above, the reaction mixture test shows <1.5% of the area by HPLC of the compound of Formula (II).

In some embodiments of the procedure described above, the reaction mixture test shows <0.2% of the area by HPLC of the compound of Formula (II).

In an embodiment of the procedure described above, the method further comprises

(i) contacting the compound of Formula (III) with a solution of sodium hydroxide to provide Compound 4; and

(ii) optionally contacting Compound 4 with an acid to provide Compound 1.

In complementary embodiments of the process described above, step (i) further comprises optionally crystallizing Compound 4 in an aqueous solution of sodium hydroxide.

In some embodiments of the procedure described above, the method further comprises

(a) dissolve Compound 4 in water and add ethyl acetate to the mixture;

(b) contacting the biphasic mixture of step (a) with an acid and separating the organic phase to provide Compound 1.

In certain embodiments, the acid of step (b) is clorlddric acid, bromydric acid, acetic acid, sulfuric acid or phosphoric acid. In some specific embodiments, the acid in step (b) is bromydric acid.

In some embodiments of the process described above, the process further comprises the recrystallization of Compound 1 in ethyl acetate. In such an embodiment, the process further comprises optionally adding n-heptane to the mixture.

Compound 3 is described herein, obtainable by the procedure described above, and having the structure:

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image8

Compound 3-A is described herein, obtainable by the procedure described above, and having the structure:

image9

Compound 4, obtainable by the procedures described above, is described herein. In some cases, Compound 4 is a crystalline polymorph characterized by peaks at 4.90, 9.83, and 25.29 ° 29 ± 0.1 ° 29. In some cases, Compound 4 is form A of the crystalline polymorph.

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Compound 1, obtainable by the procedure described above, is described herein.

Compound 1 having no more than 0.1% of Compound 2 in the area in an HPLC assay is described herein.

image10

(Compound 2)

In one case, Compound 1 having no more than 0.1% of Compound 2 is obtained by the procedures described above.

In another case, Compound 1 is described herein, which has no more than 0.1% of Compound 3 in the area in an HPLC assay.

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In one case, Compound 1 having no more than 0.1% of Compound 3 is obtained by the procedures described above.

In a complementary case, Compound 1 is described herein, which has no more than 0.1% of Compound 2, and no more than 0.1% of Compound 3 in the area in an HPLC assay.

In some cases, Compound 1 is a crystalline polymorph characterized by peaks at 10.32, 18.84 and 20.75 ° 29 ± 0.1 ° 29. In certain cases, Compound 1 is form 1 of the crystalline polymorph. In other cases, Compound 1 is a crystalline polymorph characterized by peaks at 10.46, 18.76 and 19.83 ° 29 ± 0.1 ° 29. In certain cases, Compound 1 is form 2 of the crystalline polymorph.

A reaction mixture comprising a compound of Formula (II) or a salt thereof is provided herein.

image11

wherein R is -C1-C20 alkyl, -C1-C20 alkenyl, -C3-C10-cycloalkyl or -C3-C10-cycloalkenyl; a joking agent; and a solvent.

In certain embodiments, the brominating agent is N-bromosuccinimide (NBS). In some embodiments, the solvent is THF, DMF, acetonitrile or MTBE. In certain embodiments, the solvent is THF. In complementary or additional embodiments of the reaction mixture described above, a compound of Formula (III) is produced.

image12

wherein R is H, -C1-C20 alkyl, -C1-C20 alkenyl, -C3-C10-cycloalkyl or -C3-C10 -cycloalkenyl; a solvent; and a base.

In some embodiments, a compound of Formula (III) is produced, wherein R is -C1-C20 alkyl, -C1-C20 alkenyl, -C3-C10-cycloalkyl or -C3-C10 -cycloalkenyl.

Some cases provided herein describe a reaction mixture comprising a compound of Formula (III)

image13

Formula (III)

wherein R is H, -C1-C20 alkyl, -C1-C20 alkenyl, -C3-C10-cycloalkyl or -C3-C10 -cycloalkenyl;

In some cases of the reaction mixture described above, R is -C1-C20 alkyl, -C1-C20 alkenyl, -C3-C10-cycloalkyl or -C3-C10 -cycloalkenyl. In some cases, the solvent is water. In complementary or additional cases, the acid is bromic acid. In complementary or additional cases of the reaction mixture described above, Compound 4 is produced.

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Other cases provided herein describe a reaction mixture comprising Compound 4

image15

a solvent; and an acid.

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In some cases of the reaction mixture described above, the acid is brominated acid. In some cases, the solvent is water. In complementary or additional cases of the reaction mixture described above, Compound 1 is produced.

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image16

(Compound 1)

In one aspect, a compound of Formula (II), used in the above Procedure 1, is prepared by a procedure (Procedure 2) comprising contacting a compound of structure:

image17

20 with a base, a solvent and a compound of Formula (IV):

OR

x \ -Xv - F

Formula (IV);

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wherein X is halo, tosylate, mesylate, triflate or besylate, and R is -C1-C20 alkyl, -C1-C20 alkenyl, -C3-C10 cycloalkyl or C3-C10-cycloalkenyl; to provide a compound of Formula (II):

image18

(II).

In some embodiments of the process described above, the compound of Formula (IV) is selected from methyl bromoacetate, ethyl bromoacetate, methyl chloroacetate and ethyl chloroacetate.

In some embodiments of the process described above, the process further comprises stirring the reaction mixture at a temperature between about 25 ° C and about 40 ° C for at least one hour.

In some embodiments of the process described above, the crude reaction product comprising a compound of Formula (II) is washed with a cooled mixture of ethyl acetate (EtOAc) and isopropanol.

A structure compound is provided herein:

image19

Compound 2 is provided herein, which has an HPLC purity of at least 98%. Compound 2 is provided herein, which has an HPLC purity of at least 99%.

In one embodiment, Compound 2, Compound 2 having an HPLC purity of at least 98% or Compound 2 having an HPLC purity of at least 99% is obtained by the procedures described above.

A structure compound is provided herein:

image20

In one embodiment, Compound 2-A is obtained by the procedure described above.

A reaction mixture comprising a compound of Formula (IV) is described herein in some cases:

or

in which X is an output group; R is H, -C1-C20 alkyl, -C1-C20 alkenyl, -C3-C10 cycloalkyl or -C3-C10 cycloalkenyl; Compound 5; one base; and a solvent. In some cases of the reaction mixture described above, the

Compound of Formula (IV) is methyl bromoacetate, ethyl bromoacetate, methyl chloroacetate or ethyl chloroacetate. In certain embodiments, a compound of Formula (II)

image21

wherein R is H, -C1-C20 alkyl, -C1-C20 alkenyl, -C3-C10 cycloalkyl or -C3-C10-cycloalkenyl is produced in the reaction mixture described above. In certain embodiments, a Compound 2 or 2-A is produced in the reaction mixture described above.

image22

(Compound 2)

image23

(Compound 2-A)

In one aspect, Compound 5, used in the Procedure 2 described above, is prepared by a method (Procedure 3) comprising

(5-i) contacting a structure compound:

(Compound 6)

with metric acid, water and a solvent to provide a compound of structure:

image24

image25

15 (5-ii) contacting Compound 7 with hydrogen, palladium on charcoal and one or more solvents for

Provide a compound structure:

image26

(5-iii) contacting Compound 8 with an acid to provide a salt of Compound 8;

(5-iv) contacting the salt of Compound 8 of step (5-iii) with a base, thiophosgene and a solvent and stir the mixture at about 5 ° C to provide a compound of structure:

(Compound 9)

(5-v) contacting Compound 9 formylhydrazine and a solvent to provide a compound of structure:

image27

image28

(Compound 10)

Y

(5-vi) contacting Compound 10 with a base, water and a solvent to provide Compound 5:

image29

In some embodiments of the process described above, the acid in step (5-iii) is selected from chlortndric acid, oxalic acid and tartaric acid. In a specific embodiment of the process described above, the acid in step (5-iii) is oxalic acid.

In one embodiment of the procedure described above, the salt of compound 8 in step (5-iv) is a salt of oxalate.

The oxalate salt of Compound 8 is described herein, and having the structure:

image30

In one case, Compound 8-A is obtained by the procedures described above.

A reaction mixture comprising Compound 9, a nucleophile and a solvent is described herein in some cases.

image31

'(Compound 9)

In some cases of the reaction mixture described above, the nucleophile is formylhydrazine. In certain cases, Compound 10 is produced in the reaction mixture described above.

image32

5 A reaction mixture comprising Compound 10, a base and a solvent is also described herein. In some cases, the base is potassium bicarbonate, potassium carbonate, sodium bicarbonate, sodium carbonate or cesium carbonate. In certain cases, Compound 5 is produced in the reaction mixture described herein.

N-N

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(Compound 5)

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In one aspect, Compound 5, used in the Procedure 2 described above is prepared by a procedure (Procedure 4) comprising

(5-i) contacting a structure compound:

image34

(Compound 6)

with nitric acid, water and a solvent to provide a compound of structure:

image35

(5-ii) contacting Compound 7 with hydrogen, palladium on charcoal and one or more solvents to provide a compound of structure:

image36

(5-iii-A) contacting Compound 8 with sodium thiocyanate, water and a solvent, and heating the mixture to a temperature of at least 130 ° C to provide a compound of structure:

(Compound 9)

5 (5-iv-A) contacting Compound 9 of step (5-iii-A) with formylhydrazine and a solvent to provide

a compound of structure:

image37

image38

(Compound 10)

Y

(5-vi) contacting Compound 10 of step (5-iv-A) with a base, water and a solvent to provide Compound 5:

image39

A compound of structure is described herein:

image40

Compound 5, obtainable by Procedure 3 or Procedure 4 described above, is described herein.

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Compound 9, obtainable by Procedure 3 or Procedure 4 described above, is described herein.

Compound 10, obtainable by Procedure 3 or Procedure 4 described above, is described herein.

Compound 1, which has at least 98% area purity in an HPLC assay, is described herein.

Compound 1 is described herein, which has at least 98% area purity in an HPLC assay and is obtained by the procedures described above. In one case, Compound 1 is prepared using Procedure 1, Procedure 2 and Procedure 3 described above. In another case, Compound 1 is prepared using Procedure 1, Procedure 2 and Procedure 4 described above.

In one aspect, a procedure (Procedure 5) for preparing is described herein.

image41

(Compound 1) or

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(Compound 4)

which includes:

(i) contact a structure compound

image43

OR

* - ^ VR

° Formula (IV)

wherein X is halo, tosylate, mesylate, triflate or besylate, and R is -C1-C20 alkyl, -C1-C20 alkenyl, -C3-C10 cycloalkyl or C3-C10-cycloalkenyl;

to provide a compound of Formula (V):

image44

Formula (V)

(ii) contacting the compound of Formula (V) with copper (II) bromide, potassium nitrite and a solvent at a temperature between about 14 ° C and about 22 ° C to provide a compound of structure:

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(iii) contacting a solution of the compound of Formula (III) of step (ii) in a solvent with aqueous sodium hydroxide solution to provide a compound of structure:

image46

Y

(iv) optionally contacting an aqueous solution of Compound 4, of step (iii), with an acid to provide a mixture comprising Compound 1.

In some cases of the procedure described above, R is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, isoamyl, pentyl, hexyl, heptyl, octyl, nonyl, terpenyl, bornyl, allyl, linalyl or geranyl.

In certain cases of the procedure described above, R is methyl or ethyl. In some specific cases of the procedure described above, R is methyl.

In some cases of the procedure described above, the compound of Formula (IV) of step (i) is selected from methyl bromoacetate, ethyl bromoacetate, methyl chloroacetate and ethyl chloroacetate.

In some cases of the procedure described above, the acid of step (iv) is clorlddric acid, bromydric acid, acetic acid, sulfuric acid or phosphoric acid. In some specific cases of the procedure described above, the acid in step (iv) is bromydric acid.

In some cases of the process described above, the process further comprises filtering the mixture of step (iv) to provide Compound 1 as a solid.

In some cases of the process described above, the process further comprises extracting the mixture from step (iv) with ethyl acetate and removing the ethyl acetate to provide Compound 1 as a solid.

In some cases of the process described above, the process further comprises recrystallizing Compound 1 in ethyl acetate.

Compound 1, obtainable by the procedure described above, is described herein.

Compound 3 is described herein, obtainable by the procedure described above, and having the structure:

image47

Compound 3-A is described herein, obtainable by the procedure described above, and having the structure:

image48

Compound 4, obtainable by the procedure described above, is described herein.

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Compound 12 is described herein, obtainable by the procedure described above, and having the structure:

image49

Compound 12-A, obtainable by the procedure described above, and having the structure is described herein:

image50

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In a complementary aspect, any of the procedures described above are suitable for the synthesis of any compound of Formula (I).

In one aspect, a process (Procedure 1a) for preparing a compound of Formula (III) is provided herein:

image51

Formula (III);

20 comprising contacting a compound of Formula (II):

image52

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wherein R is -C1-C20 alkyl, -C1-C20 alkenyl, -C3-C10-cycloalkyl or -C3-C10-cycloalkenyl; with N-bromosuccinimide (NBS) and a solvent. In some embodiments, R is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, isoamyl, pentyl, hexyl, heptyl, octyl, nonyl, terpenyl, bornyl, allyl, linalyl or geranyl. In certain embodiments, R is methyl or ethyl. In some embodiments, the compound of Formula (II), the NBS and the solvent are stirred for at least 12 hours, and at a temperature between room temperature and 32 ° C.

In some embodiments, the Procedure 1a described above further comprises contacting the compound of Formula (III) with a solution of sodium hydroxide to provide Compound 4:

image53

In certain embodiments, the process comprises crystallizing Compound 4 in the aqueous sodium hydroxide solution. In alternative embodiments, the process further comprises contacting Compound 4 with an acid to provide Compound 1:

image54

In certain embodiments, the acid is bromiduric acid. In another alternative embodiment, the process further comprises (a) dissolving Compound 4 in water and adding ethyl acetate to the mixture; and (b) contacting the biphasic mixture of step (a) with an acid and separating the organic phase to provide Compound 1.

A Compound 3 or Compound 3-A is described herein:

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(Compound 3) (Compound 3-A)

obtained by the procedures according to the Procedure 1a described above.

A compound 4 is described here:

image57

obtained by the procedures according to the Procedure 1a described above. A compound 1 is described here:

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obtained by the procedures according to the Procedure 1a described above. In some cases, Compound 1 is a crystalline polymorph characterized by peaks at 10.46, 18.76, and 19.83o29 ± 0.1 ° 29. In certain cases, Compound 1 is form 2 of the crystalline polymorph.

In another aspect, a reaction mixture comprising a compound of Formula (II) is provided here:

image59

wherein R is -C1-C20 alkyl, -C1-C20 alkenyl, -C3-C10-cycloalkyl or -C3-C10-cycloalkenyl; a joking agent; and a solvent. In some embodiments, the brominating agent is N-bromosuccinimide (NBS).

A reaction mixture comprising a compound of Formula (III) is described herein.

image60

Formula (III);

wherein R is -C1-C20 alkyl, -C1-C20 alkenyl, -C3-C10-cycloalkyl or -C3-C10-cycloalkenyl; one base; and a solvent. In some cases, the base is sodium hydroxide.

A reaction mixture comprising Compound 4 is described herein:

image61

an acid; and a solvent. In some cases, the acid is bromhydric acid.

In one aspect, a process is provided herein (Procedure 2a) in which the compound of Formula (II), used in Procedure 1a above, is prepared by a method comprising contacting compound 5:

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image62

with a base, a solvent and a compound of Formula (IV):

Formula (IV);

in which:

X is halo, tosylate, mesylate, triflate or besylate; Y

R is -C1-C20 alkyl, -C1-C20 alkenyl, -C3-C10-cycloalkyl or -C3-C10-cycloalkenyl.

In some embodiments, the compound of Formula (IV) is selected from methyl bromoacetate, ethyl bromoacetate, methyl chloroacetate and ethyl chloroacetate. In certain embodiments, a crude reaction product comprising a compound of Formula (II) is washed with a cooled mixture of ethyl acetate and isopropanol.

A Compound 2 or Compound 2-A is also provided herein:

image63

(Compound 2)

image64

(Compound 2-A)

In certain embodiments, Compound 2 or Compound 2-A are obtained by the procedures according to Procedure 2a described above.

In another aspect, a reaction mixture comprising Compound 5 is provided herein

image65

a compound of Formula (IV):

OR

X

Formula (IV);

in which:

X is an output group; and

R is -C1-C20 alkyl, -C1-C20 alkenyl, -C3-C10-cycloalkyl or -C3-C10 -cycloalkenyl;

one base; and a solvent. In some embodiments, the compound of Formula (IV) is methyl bromoacetate, ethyl bromoacetate, methyl chloroacetate or ethyl chloroacetate.

In another aspect, there is provided herein a procedure (Procedure 3a) in which Compound 5, used in Procedure 2a above, is prepared by a procedure comprising:

(5-i) contact Compound 6:

(Compound 6);

5 with metric acid, water and a solvent to provide Compound 7:

(Compound 7);

(5-ii) contacting Compound 7 with hydrogen, palladium on charcoal and one or more solvents to provide Compound 8:

NH,

(Compound 8);

10 (5-iii) contacting Compound 8 with an acid to provide a salt of Compound 8;

(5-iv) contacting the salt of Compound 8 of step (5-iii) with a base, thiophosgene and a solvent to provide Compound 9:

image66

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(5-v) contacting Compound 9 with formylhydrazine and a solvent to provide Compound 10:

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(Compound 10);

Y

(5-vi) contacting Compound 10 with a base, water and a solvent to provide Compound 5:

image71

5 A compound selected from Compounds I-X is described herein:

2- (4- (4-Cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthium) acetic acid (Compound I); 2- (4- (4-Cyclopropylnaphthalen-1- yl) -5-hydroxy-4H-1,2,4-triazol-3-ylthio) acetic acid (Compound II); 2- (5-amino-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthium) acetic acid (Compound III); 2- (5-Bromo-4- (1-cyclopropylnaphthalen-2-yl) -4H-1,2,4-triazol-3-ylthium) acetic acid (Compound IV); 2- (5-Bromo-4- (4-methylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthio) acetic acid (Compound V); 2- (5- 10 Bromo-4- (4-propylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthium) acetic acid (Compound VI); 2- (5-Bromo-4- (5- cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthium) acetic acid (Compound VII); 2- (5-Bromo-4- (naphthalen-1-yl) -4H-1,2,4-triazol-3-ylthio) acetic acid (Compound VIII); 2- (5-Chloro-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylth) acetic acid (Compound IX); and 4- (5- (carboxymethylthio) -4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylamino) -4-oxobutanoic acid (Compound X). In some embodiments, a sample of 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-15 triazol-3-ylthium) acetic acid comprises less than about 2%, less than about 1.5%, less than about 1.0%, less than about 0.5%, less than about 0.4%, less than

about 0.3%, less than about 0.2%, less than about 0.1%, less than

approximately 0.05%, less than 0.02% of any one of Compounds I-X. In preferred cases, a sample of 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthium) acetic acid comprises less than about 0.5 % of any one of Compounds IX.

Brief description of the drawings

The new features of the invention are indicated with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the detailed description indicating illustrative embodiments, in which the principles of the invention are used, and the accompanying drawings of which:

FIGURE 1 represents an X-ray diffraction pattern of the powder of the polymorphic form 1 (raw data).

FIGURE 2 depicts an X-ray diffraction pattern of powder of polymorphic form 1 (subtracted bottom and Ka2

separated).

FIGURE 3 depicts a differential scanning calorimetry pattern of polymorphic form 1.

FIGURE 4 represents thermogravimetric analysis (a) Rep 1 and (b) Rep 2 of the polymorph 1 form.

FIGURE 5 represents an X-ray diffraction pattern of the powder of polymorphic form 2 (raw data).

FIGURE 6 depicts an X-ray diffraction pattern of the powder of polymorphic form 2 (subtracted bottom and Ka2

separated).

FIGURE 7 depicts an overlap of X-ray diffraction patterns of the powder of polymorphic form 1 (lower) and polymorphic form 2 (upper).

FIGURE 8 represents a differential scanning calorimetry pattern of polymorphic form 2.

FIGURE 9 represents a 1H NMR spectrum (DMSO-d6) of polymorph form 2.

FIGURE 10 represents an HPLC plot of polymorphic form 2.

FIGURE 11 depicts a thermogravimetric thermogram plot of polymorphic form 2.

FIGURE 12 represents a gravimetric study of vapor sorption of polymorphic form 1 and 2.

FIGURE 13 depicts an X-ray diffraction pattern of the powder of polymorphic form A.

FIGURE 14 depicts a differential scanning calorimetry pattern of polymorphic A shape.

5 FIGURE 15 represents an infrared spectrum of the polymorphic A form.

FIGURE 16 represents a Raman spectrum of the polymorphic A shape.

FIGURE 17 depicts an X-ray diffraction pattern of the powder of polymorphic B form.

FIGURE 18 depicts a differential scanning calorimetry pattern of polymorphic B shape.

FIGURE 19 depicts an X-ray diffraction pattern of the powder of the polymorphic form B '.

10 FIGURE 20 depicts a differential scanning calorimetry pattern of the polymorphic form B '.

Detailed description of the invention

Appropriate manufacturing practices are usually required for the large-scale manufacturing of possible chemically useful drugs. Certain methods and methods for the manufacture of compounds of Formula (I) are described herein:

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image72

in which

R is H, -C1-C20 alkyl, -C1-C20 alkenyl, -C3-C10 cycloalkyl, -C3-C10 cycloalkenyl or R is a conjugated ion; and Y is H, OH, NH2, F, Cl, Br or I.

The synthetic methods and methods provided herein overcome certain manufacturing disadvantages and allow the synthesis of high purity compounds while reducing waste and / or by-products, and reducing the use of corrosive materials. The improved methods and methods of synthesis of the compounds of Formula (I) described herein allow large-scale production in accordance with the guidelines of appropriate manufacturing practices (GMP).

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Certain thermal terminology

Unless otherwise defined, all the technical and scientific terms used herein have the same meaning that is commonly understood by an expert in the specialty to which the claimed subject matter belongs. In the event that there is a plurality of definitions for the terms herein, those of this section prevail.

It is to be understood that the preceding general description and the following detailed description are only exemplary and explanatory and not restrictive of any claimed subject matter. On request, the use of the singular includes the plural unless specifically indicated otherwise. Sr should point out that, as used in the specification and the appended claims, the singular forms "a", "one (a)" and "the" include plural references unless the context clearly dictates otherwise. It should be noted that the use of "or" means "and / or" unless otherwise indicated. On the other hand, the use of the term "which includes" as well as other forms, such as "include", "includes" and "included" is not limiting.

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The definition of standard chemical terms can be found in reference work, including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED." Vols A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, IR and UV / Vis spectroscopy and pharmacology are used within the specialty's experience. Unless other definitions are provided, the nomenclature used herein are the standard definitions. Standard techniques can be used for chemical syntheses, chemical analyzes, pharmaceutical preparation, formulation and distribution and treatment of individuals. The reactions and purification techniques can be performed, e.g. For example, using cases of the manufacturer's specifications or as they are carried out in the specialty or as described herein. The above techniques and procedures can generally be performed by conventional methods well known in the art and as described in various general and more specific references cited and analyzed throughout the present specification. Throughout the specification, the groups and substituents thereof can be chosen by one skilled in the art to provide stable moieties and compounds.

When the substituent groups are specified by their conventional chemical formulas, written from left to right, they also encompass chemically identical substituents that result from writing the structure from right to left. As a non-limiting example, -CH2O- is equivalent to -OCH2-.

Unless otherwise noted, the use of general chemical terms, such as although not limited to "alkyl," "amine," "aryl," are equivalent to their optionally substituted forms. For example, "alkyl" as used herein, includes optionally substituted alkyl.

In some cases, the compounds presented here possess one or more stereocenters. In some cases, the stereocenter is in the R configuration, the S configuration or combinations thereof. In some cases, the compounds presented here possess one or more double bonds. In some cases, the compounds presented here have one or more double bonds where each double bond exists in the E (trans) or Z (cis) configuration or combinations thereof. It should be understood that the presentation of a stereoisomer, regioisomer, diastereoisomer, enantiomer or particular epimer includes all possible stereoisomers, regioisomers, diastereisomers, enantiomers or epfomers and mixtures thereof. Thus, the compounds presented here include all forms of stereoisomeric, regioisomeric, diastereomeric, enantiomeric and epfomeric configurations as well as the corresponding mixtures thereof. Techniques for inverting or leaving a particular stereocenter unchanged, and those for solving mixtures of stereoisomers are found, for example, in Furniss et al. (eds.), VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816; and Heller, Acc. Chem. Res. 1990, 23, 128.

The terms "remainder," "chemical moiety," "group," and "chemical group," as used herein, refer to a specific functional segment or group of a molecule. Chemical residues are often recognized chemical entities included in or added to a molecule.

The term "reactant" as used herein, refers to a nucleophile or electrophile used to create covalent connections.

The term "bond" or "single bond" refers to a chemical bond between two atoms or two moieties when atoms linked by the link are considered to be part of a larger structure.

The term "optional" or "optionally" means that the event or circumstance described below may or may not occur, and that the description includes cases in which said event or circumstance occurs and cases in which it does not. For example, "optionally substituted alkyl" means either "alkyl" or "substituted alkyl" as defined below. In addition, an optionally substituted group may be unsubstituted (e.g., -CH2CH3), completely substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F) or substituted at any level between completely substituted and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). It will be understood by those skilled in the art with respect to any group containing one or more substituents that such groups are not intended to introduce any substitution or substitution patterns (e.g., substituted alkyl includes optionally substituted cycloalkyl groups, which at their instead of being defined as including optionally substituted alkyl groups, potentially to infinity) that are sterically impractical and / or synthetically unfeasible. Thus, it should generally be understood that any described substituents have a maximum molecular weight of about 1,000 daltons and, more typically, up to about 500 daltons (except in cases where macromolecular substituents are clearly intended, e.g., polypeptides, polysaccharides , polyethylene glycols, DNA, RNA and the like).

As used herein, C-i-Cx includes C1-C2, C1-C3 ... C-i-Cx. By way of example only, a group labeled "C1-C4" indicates that there are one to four carbon atoms in the rest, that is groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms, as well as the C1-C2 and C1-C3 intervals. Thus, by way of example only, "C1-C4 alkyl" indicates that there are one to four carbon atoms in the alkyl group, that is, the alkyl group is selected from methyl, ethyl, propyl, iso-propyl, n -butyl, iso-butyl, sec-butyl and t-butyl. Whenever it appears here, a numerical range such as "1 to 10" refers to

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each integer in the given interval; p. ex. from "1 to 10 carbon atoms" means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms.

The term "alkyl", as used herein, alone or in combination, refers to an optionally substituted linear chain saturated or optionally substituted branched chain hydrocarbon monomer having one to about ten carbon atoms, more preferably of one to six carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2- propyl, 2-methyl-1-butyl, 3-methyl-1-butyl , 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1 -pentyl, 3-methyl-1-pentyl, 4- methyl-1 -pentyl, 2-methyl-2-pentyl , 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1- butyl, n-butyl, isobutyl , sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups such as heptyl, octyl and the like. Whenever it appears herein, a numerical range such as "C1-C6 alkyl" or "C1-6 alkyl" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 atoms carbon, 5 carbon atoms or 6 carbon atoms, although this definition also covers the presence of the term "alkyl" when no numerical range is indicated.

The term "alkylene", as used herein, alone or in combination, refers to a dirradical derived from the monorradical alkyl defined above. Examples include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), isopropylene (-CH (CH3) CH2-) and the like.

The term "alkenyl", as used herein, alone or in combination, refers to an optionally substituted linear chain or optionally substituted branched chain hydrocarbon monorradical having one or more carbon-carbon double bonds and having two to about ten carbon atoms, more preferably two to about six carbon atoms. The group can be in the conformation either cis or trans around the double or double bonds, and it should be understood that it includes both isomers. Examples include, but are not limited to, ethenyl (-CH = CH2), 1-propenyl (-CH2CH = CH2), isopropenyl [-C (CH3) = CH2], butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range such as "C2-C6 alkenyl" or "C2-6 alkenyl" means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 atoms carbon or 6 carbon atoms, although the present definition also covers the presence of the term "alkenyl" when no numerical range is indicated.

The term "alkenylene", as used herein, alone or in combination, refers to a dirradical derived from the monorradical alkenyl defined above. Examples include, but are not limited to, ethenylene (-CH = CH-), propethylene isomers (eg, -CH2CH = CH- and -C (CH3) = CH-) and the like.

The term "aliphatic", as used herein, alone or in combination, refers to a saturated non-aromatic, partially unsaturated or fully unsaturated, adyclic, straight chain or branched chain, optionally substituted hydrocarbon. Thus, the term collectively includes alkyl, alkenyl and alkynyl groups.

The term "carbon chain", as used herein, alone or in combination, refers to any alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl or heteroalkynyl group, which is linear, cyclic or any combination thereof. If the chain is part of a connector and that connector comprises one or more rings as part of the central main chain, for the purpose of calculating the length of the chain, the "chain" only includes the carbon atoms that make up the lower part or the top of a given ring and not both, and when the top and bottom of the ring or rings are not of equivalent length, the shortest distance will be used to determine the length of the chain. If the chain contains heteroatoms as part of the main chain, those atoms are not calculated as part of the length of the carbon chain.

The terms "cycle," "cyclic," "ring," and "member ring," as used herein, alone or in combination, refer to any covalently closed structure, including allyclic, heterodyl, condensed or non-condensed ring systems. , aromatic, heteroaromatic and polycyclic as described herein. The rings may be optionally substituted. The rings can be part of a condensed ring system. It is understood that the term "of members" indicates the number of atoms of the skeleton that constitute the ring. Thus, by way of example only, cyclohexane, pyridine, pyran and pyrimidine are six-membered rings and cyclopentane, pyrrole, tetrahydrofuran and thiophene are five-membered rings.

The term "condensate", as used herein, alone or in combination, refers to dical structures in which the two or more rings share one or more bonds.

The term "cycloalkyl", as used herein, alone or in combination, refers to an optionally substituted saturated hydrocarbon monoraxical ring containing from three to about fifteen ring carbon atoms or from three to about ten carbon atoms of ring, although it may include carbon atoms that are not additional ring substituents (eg, methylcyclopropyl). Whenever it appears herein, a numerical range such as "C3-C6 cycloalkyl" or "C3-6 cycloalkyl" means that the cycloalkyl group may consist of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 atoms carbon, that is, it is cyclopropyl, cyclobutyl, cyclopentyl or cycloheptyl, although the present definition also covers the presence

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of the term "cycloalkyl" when a numerical interval is not indicated. The term includes condensed, non-condensed, bridged and spiro type radicals. A condensed cycloalkyl may contain from two to four condensed rings in which the ligament ring is a cycloalkyl ring, and the other individual rings may be alicyclic, heterodclic, aromatic, heteroaromatic or any combination thereof. Examples include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, decalinyl and bicyclo [2,2.1] heptyl and adamantyl ring systems. Illustrative examples include, but are not limited to, the following remains:

>. □. O ■ O ■ O ■ O 'GO-

or> -a> -aoOOO-CO-

and the like

The term "cycloalkenyl", as used herein, alone or in combination, refers to an optionally substituted hydrocarbon non-aromatic monoraradical ring having one or more carbon-carbon double bonds and three to about twenty ring carbon atoms , from three to about twelve ring carbon atoms or from three to about ten ring carbon atoms. The term includes condensed, non-condensed, bridged or spiro radicals. A condensed cycloalkenyl may contain two to four condensed rings where the ligament ring is a cycloalkenyl ring, and the other individual rings may be allyclic, heterodclic, aromatic, heteroaromatic or any combination thereof. Condensed ring systems may be condensed through a bond that is a carbon-carbon single bond or a carbon-carbon double bond. Examples of cycloalkenyls include, but are not limited to, cyclohexenyl, cyclopentadienyl and bicyclo [2,2.1] hept-2-ene ring systems. Illustrative examples include, but are not limited to the following remains:

image73

and the like

The terms "alicyclyl" or "alicyclic", as used herein, alone or in combination, refer to an optionally substituted unsaturated, partially unsaturated or completely unsaturated unsaturated hydrocarbon ring system containing from three to about twenty carbon atoms. ring, three to about twelve ring carbon atoms or three to about ten ring carbon atoms. Thus, the terms collectively include cycloalkyl and cycloalkenyl groups.

The term "carbocyclyl," as used herein, alone or in combination, refers collectively to alicyclyl and aryl groups; that is to say covalently closed annular structures fully carbonated, which can be saturated, partially unsaturated, totally unsaturated or aromatic. The carbodic rings may consist of three, four, five, six, site, eight, nine or more than nine carbon atoms. The carbocycles can be optionally substituted. The term distinguishes carbodic heterodical rings in which the main chain of the ring contains at least one atom that is different from carbon.

The terms "halogen", "halo" or "halide", as used herein, alone or in combination, refer to fluoro, chloro, bromo and iodo.

The term "hydroxy", as used herein, alone or in combination, refers to the monoraxical -OH.

The terms "carboxy" or "carboxy", as used herein, alone or in combination, refer to the remainder - C (O) OH, which can also be written as -COOH. A "carboxylate anion" is a deprotonated carboxyl moiety and is written as -COO or -COO-.

It should be understood that in cases where two or more radicals are used in succession to define a substituent linked to a structure, it is considered that the first radical named is terminal and it is considered that the last radical named is linked to the structure in question. Thus, for example, the arylalkyl radical is linked to the structure in question by the alkyl group.

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present, "4- (4-Rc-naphthalen-1-yl) -4H-1,2,4-triazole disubstituted in 3.5" refers to:

present, "5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazole substituted in 3" refers to:

image76

As used in the

image77

As used in the

The term "polymorphic form 1" refers to a crystalline form of 2- (5-bromo-4- (4-cyclopropyl naphthalen-1-yl) -4H-1,2,4-triazol-3-ylthium) acetic acid which exhibits a powder X-ray diffraction pattern substantially the same as that shown in FIGURE 1 and / or FIGURE 2 and / or a differential scanning calorimetry profile substantially the same as that shown in FIGURE 3.

The term "polymorphic form 2" refers to a crystalline form of 2- (5-bromo-4- (4-cyclopropyl naphthalen-1-yl) -4H-1,2,4-triazol-3-ylthium) acetic acid which exhibits a powder X-ray diffraction pattern substantially the same as that shown in FIGURE 5 and / or FIGURE 6 and / or a differential scanning calorimetry profile substantially the same as that shown in FIGURE 8.

The term "polymorphic form A" refers to a crystalline form of 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthio) sodium acetate which it exhibits a powder X-ray diffraction pattern substantially the same as that shown in FIGURE 13 and / or a differential scanning calorimet profile substantially the same as that shown in FIGURE 14.

The term "polymorphic form B" refers to a crystalline form of 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthio) sodium acetate which It exhibits a powder X-ray diffraction pattern substantially the same as that shown in FIGURE 17 and / or a differential scanning calorimet profile substantially the same as that shown in FIGURE 18.

The term "polymorphic form B" refers to a crystalline form of 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthio) sodium acetate which exhibits a powder X-ray diffraction pattern substantially the same as that shown in FIGURE 19 and / or a differential scanning calorimetry profile substantially the same as that shown in FIGURE 20.

As used herein, a "conjugated ion" is an ion whose presence allows the formation of a neutrally charged global species. According to this, in one case, a conjugated ion is a positively charged ion, e.g. eg, for a compound of Formula (I), which balances the negative charge associated with a carboxylate anion of a compound of Formula (I) and allows the formation of a neutrally charged global species. Examples of conjugated ions for compounds of Formula (I) include and are not limited to Na +, K +, Li +, Cs +, Mg ++, Fe +++, Al +++ or any other pharmaceutically acceptable organic or inorganic cation. When the cation has more than one loading unit (e.g., Mg ++), it is understood that one or more anionic carboxylate moieties (e.g., carboxylate moieties of compounds of Formula (I)) will be needed to form a Neutrally globally charged species. In another case, a conjugated ion is a negatively charged ion. For example, for Compound 8, a negatively charged conjugated ion balances the positive charge associated with a protonated form of Compound 8. Examples of such negatively charged conjugated ions include and are not limited to oxalate, citrate, tartrate, acetate, chloride, bromide. , fluoride or any other pharmaceutically acceptable organic or inorganic anion.

Initial attempts

Initial efforts to identify the optimal conditions for the synthesis of compounds of Formula (I) including, p. For example, Compound 1 and Compound 4 focused on Compound 11 (3-amino-4- (4- cyclopropylnaphthalen-1-yl) -1H-1,2,4-triazol-5 (4H) -thiona) as The raw material. Scheme 1 shows an exemplary synthesis of Compound 1 and Compound 4.

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Scheme 1

image78

Formula (IV)

1. NaOH / H20

2. AcOH

Formula (V)

Formula (III)

NaOH / BUO

2. EtOAc / n-hep

Starting from Compound 11, a reaction with a compound of Formula (IV) in the presence of DMF as a solvent provides a compound of Formula (V). Any reagent of Formula (IV) can be used. In a case,

The reaction of Compound 11 is carried out with methyl bromoacetate

image79

0 or methyl chloroacetate

to provide a compound of Formula (V) in which R is methyl (Compound 2). In a case

jl ■

different, the reaction of Compound 11 is carried out with ethyl bromoacetate

or

or chloroacetate of

ethyl

to provide a compound of Formula (V) in which R is ethyl (Compound 2-A). In other

OH

OR

Br ^ Ac

case, the reaction of Compound 11 is Nevated with bromoacetic acid to provide a

compound of Formula (V) in which R is H. Any suitable solvent is used. In one case, the solvent is DMF. In alternative cases, the solvent is dioxane, acetonitrile, chloroform, dichloromethane, tetrahydrofuran (THF), N-methylpyrrolidone (NMP), dimethylsulfoxide (DMSO) and the like.

The compound of Formula (V) is then subjected to a reaction with copper (II) bromide in the presence of potassium nitrite and a solvent and the reaction temperature is maintained at approximately room temperature or lower, to provide a compound of Formula ( III). In some cases, the compound of Formula (V) is subjected to CuCh / KNo2, CuCh / NaNO2, CuBr2 / NaNO2, pTsOH / NaNO2 / KBr or Br2. In one case, the reaction temperature is between about 14 ° C and about 22 ° C. In another case, the reaction temperature is between about 12 ° C and about 25 ° C. Any suitable solvent is used. In one case, the solvent is acetonitrile. In a different case, the solvent is dichloromethane, NMP, dioxane, THF and the like. In one case, the reaction provides a compound of Formula (III) that is Compound 3. In another case, the reaction provides a compound of Formula (III) that is Compound 3-A. In another case where R is H, the reaction provides Compound 1.

It is contemplated within the scope of the compounds of Formula (III) ester compounds that are prodrugs of Compound 1. Examples of such esters include and are not limited to metallic, ethyl, propylene, isopropyl, butyl, isobutyl, tert-butnic esters, isoamico, pentNico, hexNico, heptNico, octNico, nomlico, terpemlico, bormlico, alflico, linalflico and / or geramlico.

The ester group in the compound of Formula (III) is hydrolyzed using any suitable acid including and not limited to acetic, trifluoroacetic, sulfuric, metric, phosphoric, hydrochloric or bromhydric acid to provide Compound 1.

Compound 1 is then converted into a salt. In one case, Compound 1 is stirred in aqueous sodium hydroxide to provide Compound 4. In some cases, Compound 4 is a crystalline polymorph characterized by peaks at 4.90, 9.83 and 25.29 ° 20 ± O, 1st 20. In some cases, Compound 4 is form A of the crystalline polymorph. In alternative cases, Compound 1 is stirred in potassium hydroxide, lithium hydroxide, hydroxide

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of aqueous cesium or any other basic solution suitable for providing a compound of Formula (I) in which R is a conjugated ion. In some of such cases, an alcohol (eg, methanol, ethanol, isopropanol) is used as a co-solvent for the reaction step comprising the conversion of Compound 1 into a salt.

An aqueous solution of Compound 4 (or the compound of Formula (I) in which R is a conjugated ion) is acidified using a suitable acid such as hydrobromic acid. Other acids that are suitable for this stage include and are not limited to acetic, trifluoroacetic, sulfuric, metric, phosphoric, hydrochloric acid and the like. The mixture is extracted with a suitable organic solvent such as ethyl acetate. Other solvents suitable for extraction include and are not limited to dichloromethane, tert-butyl methyl ether, tert-butanol and the like. Next, Compound 1 is optionally recrystallized from EtOAc. In some cases, Compound 1 is recrystallized from ethyl acetate and using n-heptanes as a counter solvent. It will be appreciated that any other solvent or combination of solvents suitable for recrystallization of Compound 1 can be used.

In some cases, Compound 1 is a crystalline polymorph characterized by peaks at 10.32, 18.84 and 20.75 ° 20 ± 0.1 ° 20. In certain cases, Compound 1 is form 1 of the crystalline polymorph. In other cases, Compound 1 is a crystalline polymorph characterized by peaks at 10.46, 18.76 and 19.83 ° 20 ± 0.1 ° 20. In certain cases, Compound 1 is form 2 of the crystalline polymorph.

Synthesis of Compound 11 - first method

The synthesis of Compound 11, described in Scheme 1, was achieved, in an exemplary case, using the reaction sequence described in Scheme 2.

Scheme 2

image80

Starting from 1-bromonaphthalene, a reaction with a suitable Grignard reagent provides Compound 6. Compound 11 is then prepared by a procedure (Procedure 6) comprising

(11 -i) contacting Compound 7 with hydrogen, palladium on charcoal, in one or more suitable solvents to provide a compound of structure:

image81

(Compound 8);

(11-ii) contacting Compound 8 with oxalic acid to provide an oxalate salt of Compound 8;

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(11-iii) contacting the oxalate salt of Compound 8, of step (11 -i), with a base, thiophosgene and a solvent and stirring the mixture at a temperature below room temperature to provide a compound of structure:

image82

(11-iv) contacting Compound 9 from step (11-iii) with aminoguanidine hydrochloride and a base and a solvent to provide a compound of structure:

image83

Y

(11-v) contacting Compound 13 of step (11-iv) with a base, water and a solvent to provide Compound 11.

Compound 9, prepared by Method 6 described above, is described herein. Compound 11, prepared by Method 6 described above, is described herein. Compound 13, prepared by Procedure 6 described above, is described herein.

In one case, a solvent suitable for use in step (11-i) of Procedure 6 described above is methanol, ethanol or dichlorobenzene or any combination thereof. In one case, a solvent suitable for use in step (11-i) of Procedure 6 is methanol. In another case, a solvent suitable for use in step (11-i) of Procedure 6 is ethanol. Alternative solvents such as, for example, THF are also contemplated within the scope presented herein.

The use of other acids and / or acid salts in step (11-ii) and (11-iii) of Procedure 6 described above is described herein, including and not limited to the use of cfric acid, tartaric acid, acid acetic acid, hydrochloric acid and the like for the preparation of the corresponding acid salts of Compound 8.

In one case, a solvent suitable for use in step (11-iii) of Procedure 6 is toluene. In alternative cases, a solvent suitable for use in step (11-iii) of Procedure 6 is dichlorobenzene, dichloromethane, xylenes or any other suitable solvent. In some cases, the reaction mixture of step (11-iii) of Procedure 6 is stirred at a temperature between about 0 ° C and about 10 ° C, between about 5 ° C and about 15 ° C or between about 5 ° C and approximately 25 ° C. In some cases, the reaction mixture of step (11-iii) of Procedure 6 is stirred at about 5 ° C. In some cases, the reaction mixture of step (11-iii) of Procedure 6 is stirred at approximately room temperature.

In additional cases, a suitable base for the reaction of step (11-iii) of Procedure 6 is selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, potassium phosphate or any other suitable base. In some cases, a suitable base for the reaction of step (11-iii) of Procedure 6 is potassium hydroxide.

In additional cases, a suitable basis for the reaction of step (11-iv) of Procedure 6 is an organic or inorganic base. Non-limiting examples include triethylamine, diisopropylamine, diisopropylethylamine, potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, potassium phosphate or any other suitable base. In one case, the reaction of step (11-iv) of Procedure 6 described above is carried out.

carried out in the presence of diisopropylethylamine (DIEA) or sodium hydroxide. Any suitable solvent is selected for the reaction of step (11 -iv) of Procedure 6 including, for example, DMF, THF, acetonitrile, dioxane, NMP or the like. In one case, the reaction of step (11 -iv) of Procedure 6 is carried out in DMF.

5 In one case, a solvent suitable for use in step (11-v) of Procedure 6 is DMF. In alternative cases, a solvent suitable for use in step (11-v) of Procedure 6 is toluene, dichlorobenzene, xylenes, NMP, acetonitrile, dioxane or any other suitable solvent. In additional cases, a suitable base for the reaction of step (11-v) of Procedure 6 is selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, potassium phosphate or any other suitable base. In some cases, a suitable base for the reaction of step (11-v) of Procedure 6 is sodium hydroxide.

Synthesis of Compound 11 - second method

In a different case, the synthesis of Compound 11, described in Scheme 1, was achieved using the reaction sequence described in Scheme 3.

Scheme 3

fifteen

image84

1. Hydrazine hydrate, methanol- -

—MgBr

2. HCI MTBE

[NiCI2 (dppp)]:

THF

DCM or toluene

2. MTBE

NaOH

Starting with 1-bromonaphthalene, a reaction with a suitable Grignard reagent provides Compound 6.

Compound 11 is then prepared by a procedure (Procedure 7) comprising

20 (11 -i-A) contacting Compound 7 with hydrazine hydrate and a solvent to provide a compound

of structure:

image85

(11-ii-A) contacting Compound 8 with hydrochloric acid and a solvent to provide a hydrochloride salt of Compound 8;

(11-iii-A) protect the amine group in the salt of step (11-ii-A) to provide a compound of structure:

image86

5 (11-iv-A) contacting Compound 14 with hydrochloric acid and ethanol to provide a hydrochloride salt

of Compound 8;

(11-v-A) contacting the hydrochloride salt of Compound 8 from step (11-iv-A) with a base, thiophosgene and a solvent to provide a compound of structure:

image87

10 (11-vi-A) contacting Compound 9 from step (11-v-A) with aminoguanidine hydrochloride, a

base and a solvent to provide a compound of structure:

image88

Y

(11-vii-A) contacting Compound 13 from step (11-vi-A) with a base, water and a solvent 15 to provide Compound 11.

Compound 9, prepared by Method 7 described above, is described herein. Be

described herein Compound 11, prepared by the Procedure 7 described above. Be

described herein Compound 13, prepared by Procedure 7 described above. Be

described herein Compound 14, prepared by Procedure 7 described above.

A hydrogen chloride salt of Compound 8, obtainable by Method 7 described above and having the structure is described herein:

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image89

(Compound 8-B)

In one case, a solvent suitable for use in step (11-i-A) of Procedure 7 described above is methanol, ethanol or dichlorobenzene or any combination thereof. In one case, a solvent suitable for use in step (11-i-A) of Procedure 7 is methanol. In another case, a solvent suitable for use in step (11-i-A) of Procedure 7 is ethanol. Alternative solvents such as, for example, THF are also presented herein.

The use of other acids and / or acid salts is described herein in step (11-ii-A), (11-iii-A) and (11-vA) of Procedure 7 described above, including but not limited to to the use of cfric acid, tartaric acid, acetic acid, hydrochloric acid and the like, for the preparation of the corresponding acid salts of Compound 8. The use of a suitable solvent is described herein in step (11-ii-A ) of Procedure 7 including THF, dioxane, diethyl ether, methyl tert-butyl ether (MTBE) or the like. In one case, a solvent used in step (11- ii-A) of Procedure 7 is MTBE.

In one case, a protecting group used in step (11-iii-A) of Procedure 7 is tert-butyloxycarbonyl. Any other suitable amine protecting group can be used. In one case, the reaction of step (11-iii-A) of Procedure 7 is carried out in the presence of butyloxycarbonyl anhydride, ethanol, triethylamine and MTBE to provide Compound 14.

In one case, a solvent suitable for use in step (11-v-A) of Procedure 7 is dichloromethane. In alternative cases, a solvent suitable for use in step (11-v-A) of Procedure 7 is toluene, dichlorobenzene, xylenes or any other suitable solvent. In some cases, the reaction mixture of step (11-vA) of Procedure 7 is stirred at a temperature between about 0 ° C and about 10 ° C, between about 5 ° C and about 15 ° C or between about 5 ° C and approximately 25 ° C. In some cases, the reaction mixture of step (11-v-A) of Procedure 7 is stirred at approximately 5 ° C. In some cases, the reaction mixture of step (11-v-A) of Procedure 7 is stirred at approximately room temperature.

In additional cases, a suitable base for the reaction of step (11-v-A) of Procedure 7 is selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, potassium phosphate or any other suitable base. In some cases, a suitable base for the reaction of step (11-v-A) of Procedure 7 is potassium hydroxide.

In additional cases, a suitable base for the reaction of step (11-vi-A) of Procedure 7 is an organic or inorganic base. Non-limiting examples include triethylamine, diisopropylamine, diisopropylethylamine, potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, potassium phosphate or any other suitable base. In one case, the reaction of step (11-vi-A) of Procedure 7 described above is carried out in the presence of diisopropylethylamine (DIEA) or sodium hydroxide. Any suitable solvent is selected for the reaction of step (11-vi-A) of Procedure 7 including, for example, DMF, THF, acetonitrile, dioxane, NMP or the like. In one case, the reaction of step (11-vi-A) of Procedure 7 is carried out in DMF.

In one case, a solvent suitable for use in step (11-vii-A) of Procedure 7 is DMF. In alternative cases, a solvent suitable for use in step (11-vii-A) of Procedure 7 is toluene, dichlorobenzene, xylenes, NMP, acetonitrile, dioxane or any other suitable solvent. In additional cases, a suitable base for the reaction of step (11-vii-A) of Procedure 7 is selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, potassium phosphate or any other suitable base . In some cases, a suitable base for the reaction of step (11-vii-A) of Procedure 7 is sodium hydroxide.

Disadvantages in initial attempts

The sequence of reactions described in Scheme 1 requires the use of copper (II) bromide that generates residual material and requires an additional expense for waste disposal. An additional disadvantage of this process is that Compound 1 is isolated twice to achieve the desired purity levels.

In addition, the synthesis of Compound 11 requires a long sequence of steps as described in Scheme 2 and Scheme 3 above, and the use of aminoguanidine hydrochloride. Withdrawal of Compound 13 also

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Requires additional purification stages. In addition, as shown in Scheme 3, Compound 8-B is added twice in order to achieve the desired purity levels for Compound 11.

Enhanced Procedures

In order to avoid the disadvantages of the procedures described above and in Schemes 1-3, alternative procedures were investigated for the synthesis of Compound of Formula (I), including Compound 1 and Compound 4. The improved procedures described below have certain advantages. The improved procedures reduce the number of stages required for the manufacture of compounds of Formula (I), including Compound 1 or Compound 4. The improved procedures allow for easier purification of the compounds sought and do not require duplicate isolates of the same compound. . The improved procedures prevent the use of aminoguanidine hydrochloride and the subsequent additional purification steps required for the removal of Compound 13. In addition, the improved procedures described below avoid the use of corrosive chemicals and reduce residues such as residues from the copper bromide reaction described in Scheme 1 above.

Accordingly, certain new procedures for the synthesis of the Compounds of Formula (I), including Compound 1 and Compound 4, were designed as described below and in the summary section of the invention. The improvement in the new procedures is the use of a compound of Formula (II) as an intermediate product for the synthesis of Compounds of Formula (I). A further improvement in the new procedure is the use of formylhydrazine, instead of aminoguanidine, for the synthesis of a triazole. The use of formylhydrazine prevents the formation of semicarbacides such as Compound 13 of the old procedure and reduces the purification steps required for the removal of intermediate semicarbacids such as Compound 13 of the old procedure.

Synthesis of Compounds of Formula (II)

In one embodiment, Scheme 4 below describes an exemplary synthesis of Compounds of Formula (II).

Scheme 4

image90

A method of synthesizing compounds of Formula (II) is provided herein in some embodiments. In some embodiments, Compound 6 is transformed into a compound of Formula (II) (eg, Compound 2). In some embodiments, Compound 6 is transformed into Compound 7. In some embodiments, Compound 7 is transformed into Compound 8. In complementary and additional embodiments, Compound 8 is transformed into Compound 9. In complementary and additional embodiments, the Compound 9 is transformed into Compound 10. In complementary or additional embodiments, Compound 10 is transformed into Compound 5. In some embodiments, Compound 5 is transformed into a compound of Formula (II).

In some embodiments, Compound 6 is transformed into Compound 7 in the presence of one or more nitration agents. Non-limiting examples of suitable nitration agents include HNO3, HNO3 with acid (e.g., H2SO4), NH4NO3 / trifluoroacetic acid, isoamyl nitrate / BF3 ^ Et2O, isoamyl nitrate / TfOH, Cu (NO3) / TFAA, AgNO3 / Tf2O and Hg (NO3) 2 / HNO3. Any suitable solvent is used for the nitration reaction. In some embodiments, a suitable solvent used for the reaction is halobenzene (eg, 1,2-dichlorobenzene), toluene, water, ionic liquids or combinations thereof.

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In some embodiments, Compound 7 is reduced to provide Compound 8 in the presence of one or more reducing agents. In some embodiments, suitable reducing agents include palladium (e.g., palladium on carbon, 5% palladium on carbon, 10% palladium on carbon, palladium on barium sulfate, palladium chloride on carbon), platinum oxide, Raquel, metallic iron in acetic acid (e.g., Fe / HCl in aqueous ethanol), FeCl3 / HCl, stannous (II) chloride in acid, metallic zinc, sodium dithionite, lithium aluminum hydride, diisobutylaluminium hydride , superhydride, samarium diiodide, metal samarium (e.g., Sm (4 equiv.) / NH4Cl in methanol), sodium sulfide (e.g., sodium sulfide / NH4Cl in aqueous NH4OH), hydrogen sulfide / base, titanium (III) chloride or any other suitable reduction method. Any suitable solvent can be used for reduction. In some embodiments, the solvent is water, acetonitrile, DMF, THF, toluene, xylenes, dioxane, butanol, methanol, ethanol, diethyl ether, acetone, hexane, pentane, heptane, ethyl acetate, dichloromethane, dichloroethane, dichlorobenzene, NMP or combinations thereof.

In one embodiment, Compound 8 which comprises an amino group is optionally converted to an acid salt. Non-limiting examples of acids that can be employed for the synthesis of acid salts of Compound 8 include oxalic acid, tartaric acid, cfric acid, formic acid, malonic acid, maleic acid, adipic acid, formic acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, benzoic acid, hydrochloric acid or any other suitable acid. In some embodiments, the free amine Compound 8 is used in additional steps.

In some embodiments, Compound 8 is transformed into Compound 9 in the presence of a thionyl transfer reagent. In some embodiments, the thionyl transfer reagent is thiophosgene. In some embodiments, Compound 8 or an acid salt thereof is converted to a thioisocyanate in the presence of thiophosgene and a suitable base. In some embodiments, the base potassium bicarbonate, potassium carbonate, potassium acetate, potassium hydroxide, sodium acetate, sodium benzoate, sodium bicarbonate, sodium carbonate, sodium hydroxide, sodium metasilicate, sodium sesquicarbonate, trisodium phosphate, calcium carbonate, calcium hydroxide, ferrous hydroxide , lithium hydroxide, barium hydroxide, cesium hydroxide, strontium hydroxide, rubidium hydroxide, cesium carbonate, potassium t-butoxide or potassium phosphate. In certain embodiments, the base is butyllithium, lithium diisopropylamide, lithium diethylamide, sodium amide, sodium hydride, lithium bis (trimethylsilyl) amide, lithium bis (trimethylsilyl) amide. In other embodiments, the base is amomac, triethylamine, propylamine, methylamine, dimethylamine, trimethylamine, methyldiethylamine, diisopropylethylamine, aniline, piperidine, pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or pyrrolidine. Any suitable solvent for the transformation of nucleophilic addition can be used.

In some embodiments, the thionyl transfer agent is carbon disulfide, sodium thiocyanate, thiocarbonyldiimidazole, potassium thiocyanate, zinc thiocyanate, silver thiocyanate or ammonium thiocyanate. In some cases, Compound 8 or a salt thereof is converted to a thioisocyanate in the presence of carbon disulfide (CS2). In complementary or additional embodiments, the reaction further comprises aqueous NH4OH, followed by the addition of lead nitrate (Pb (NO3) 2). In alternative embodiments, the reaction of Compound 8 or an acid salt thereof and CS2 further comprises a base and a solvent (eg, THF) followed by TsCl. In alternative embodiments, Compound 8 or an acid salt thereof (eg, Compound 8-A) is converted to a thioisocyanate in the presence of thiocarbonyldiimidazole and a solvent (eg, DMF). In other embodiments, Compound 8 or a salt thereof is converted to a thioisocyanate in the presence of a thiocyanate (eg, sodium thiocyanate). In certain embodiments, the reaction of Compound 8 with a thiocyanate (eg, sodium thiocyanate) provides a thiourea intermediate. In complementary or additional embodiments, the removal of the thiourea intermediate product from amomac provides Compound 9. In certain embodiments, the thiourea intermediate product is heated to high temperatures (e.g., 100 ° C, 110 ° C, 120 ° C, 130 ° C, 140 ° C, 150 ° C, 160 ° C, 170 ° C, 180 ° C, 190 ° C or 200 ° C) to provide Compound 9. In some embodiments, the solvent used for any transformation of Compound 8 in Compound 9 is acetonitrile, DMF, THF, toluene, xylenes, dioxane, butanol, methanol, ethanol, diethyl ether, acetone, hexane, pentane, heptane, ethyl acetate, dichloromethane, dichloroethane, dichlorobenzene, NMP or combinations thereof.

In some embodiments, Compound 9 is transformed into Compound 10 in the presence of a nucleophile. In some embodiments, the nucleophile is formylhydrazine. Any suitable solvent can be used for transformation by nucleophilic addition. In some embodiments, the solvent is water, acetonitrile, DMF, THF, toluene, xylenes, dioxane, butanol, methanol, ethanol, diethyl ether, acetone, hexane, pentane, heptane, ethyl acetate, dichloromethane, dichloroethane, dichlorobenzene, NMP or combinations thereof.

In some embodiments, Compound 10 is cycled to provide Compound 5 in the presence of one or more bases. Any suitable base can be used in the cyclization reaction. In some embodiments, the base is potassium bicarbonate, potassium carbonate, potassium acetate, potassium hydroxide, sodium acetate, sodium benzoate, sodium bicarbonate, sodium carbonate, sodium hydroxide, sodium metasilicate, sodium sesquicarbonate, trisodium phosphate, calcium carbonate, calcium hydroxide, hydroxide ferrous, lithium hydroxide, barium hydroxide, cesium hydroxide, strontium hydroxide, rubidium hydroxide, cesium carbonate, potassium t-butoxide or potassium phosphate. In certain embodiments, the base is butyllithium, lithium diisopropylamide, lithium diethylamide, sodium amide, sodium hydride, lithium bis (trimethylsilyl) amide, lithium bis (trimethylsilyl) amide. In other embodiments, the base is amomac, triethylamine, propylamine, methylamine, dimethylamine, trimethylamine, methyldiethylamine, diisopropylethylamine, aniline,

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piperidine, pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or pyrrolidine. Any suitable solvent for transformation by nucleophilic addition can be used. In some embodiments, the solvent is water, acetonitrile, DMF, THF, toluene, xylenes, dioxane, butanol, methanol, ethanol, diethyl ether, acetone, hexane, pentane, heptane, ethyl acetate, dichloromethane, dichloroethane, dichlorobenzene, NMP or combinations thereof.

In some embodiments, Compound 5 undergoes a nucleophilic substitution to provide a compound of

xJ ^ o "R.

Formula (II) in the presence of an electrophile. In some embodiments, the electrophile has the structure. In some embodiments, X is an output group. In certain embodiments, X is halo (e.g., bromine, iodine or chlorine), tosylate, mesylate, besylate, triflate, nonaflates, fluorosulfonates or OH. In some embodiments, R is alkyl. In other embodiments, R is C1-20 alkyl, C1-10 alkyl, C1-6 alkyl or C1-3 alkyl. In some embodiments, R is methyl, glycol, propyl, isopropyl, buffolic, isobutyl, tert-butyl, isoamyl, penffolic, hexyl, hepffolic, ocphlic, nonflico, terpenflico, bornflico, alflico, linalflico and / or geranflico ethers. In some embodiments, R is H. Any suitable solvent can be used for nucleophilic substitution transformation. In some embodiments, the solvent is water, acetonitrile, DMF, THF, toluene, xylenes, dioxane, butanol, methanol, ethanol, diethyl ether, acetone, hexane, pentane, heptane, ethyl acetate, dichloromethane, dichloroethane, dichlorobenzene, NMP or combinations thereof.

In some embodiments of the process discussed above (Scheme 4), the Compounds or intermediates are isolated and used in subsequent synthetic stages without additional purification steps. In certain embodiments, the Compounds or intermediates (eg, Compound 7, 8, 9, 10, 5 or a compound of Formula II) are used without isolation or purification steps of the intermediates. In some embodiments, the Compounds or intermediates are purified before being used in additional synthetic steps. In certain embodiments, the Compounds or intermediates are purified by crystallization. In some embodiments, the Compounds or intermediates are purified by distillation, column chromatography, reverse phase chromatography, preparative thin layer chromatography or combinations thereof.

In a complementary embodiment, Scheme 5 below describes an alternative exemplary synthesis of Compounds of Formula (II).

Scheme 5

image91

Referring to Scheme 5 described above, starting from Compound 6, a nitration reaction provides Compound 7. The nitro group in Compound 7 is reduced to an amine (Compound 8) using any suitable reduction method. In one embodiment, the reduction is carried out using gaseous hydrogen and palladium on charcoal, in the presence of a suitable solvent. In some embodiments, a catalytic amount of palladium is used (e.g., 0.001%, 0.005%, 0.01%, 0.02%, 0.05%, 0.1%, 0.2%, 0.5 %, 1%, 2%, 3%, 4%, 5% or 10%). In some embodiments, a stoichiometric amount of palladium on charcoal is used. In one embodiment, a solvent suitable for catalytic hydrogenation is selected from methanol, ethanol, tert-butanol, THF, dichlorobenzene or any combination thereof.

In one embodiment, Compound 8 comprising an amino group is converted to an acid salt (eg, oxalate salt). In one embodiment, an acid salt of the amine (Compound 8) is used in additional steps (e.g., as shown in Scheme 5).

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In one embodiment, shown in Scheme 5, Compound 8 or an acid salt thereof (e.g., Compound 8-A) is converted to a thioisocyanate (Compound 9) in the presence of thiophosgene and a base adequate. In some such embodiments, a suitable solvent for the synthesis of Compound 9 from Compound 8 or a salt thereof is toluene. In alternative embodiments, a suitable solvent for the synthesis of Compound 9 from Compound 8 or a salt thereof, according to Scheme 4, is dichlorobenzene, xylenes, dichloromethane or any other suitable solvent. In some cases, the reaction mixture is stirred at a temperature between about 0 ° C and about 10 ° C, between about 5 ° C and about 15 ° C or between about 5 ° C and about 25 ° C. In some cases, the reaction mixture is stirred between about 5 and about 100 ° C. In some cases, the reaction mixture is stirred at approximately 5 ° C. In some cases, the reaction mixture is stirred at approximately room temperature. In further embodiments, a suitable base for the synthesis of Compound 9 from Compound 8 or a salt thereof is selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, potassium phosphate or any other suitable base . In some embodiments, a suitable base for the synthesis of Compound 9 from Compound 8 or a salt thereof is potassium hydroxide.

In an alternative embodiment, the free base of Compound 8 is converted to the thioisocyanate Compound 9 in the presence of sodium thiocyanate and water. In one embodiment, the solvent used for the reaction is butanol, ethanol, water, acetonitrile, dioxane, toluene, xylenes, DCB, DMF, NMP or any other suitable solvent. In one embodiment, the reaction mixture is stirred at a temperature of at least 100 ° C, 110 ° C, 120 ° C, 130 ° C, 140 ° C or 150 ° C. In some specific embodiments, the reaction of the free base of Compound 8 with sodium thiocyanate is carried out in the presence of water and xylenes at a temperature of at least 130 ° C. Also contemplated within the scope are the embodiments presented herein the use of other thiocyanates such as potassium thiocyanate, zinc thiocyanate, silver thiocyanate, ammonium thiocyanate or other suitable reagents.

The thioisocyanate Compound 9 is converted to Compound 10 in the presence of formylhydrazine and a suitable solvent. In one embodiment, the solvent is DMF. In alternative embodiments, the solvent is acetonitrile, THF, dioxane, dichloromethane, dichlorobenzene, NMP or any other suitable solvent. Advantageously, this step avoids the formation of Compound 13 described above in Scheme 2 and Scheme 3.

Compound 10 does cycle to Compound 5 using a suitable base, water and a solvent. In one embodiment, the base is potassium bicarbonate. In alternative embodiments, the base is selected from potassium hydroxide, sodium hydroxide, sodium bicarbonate, lithium hydroxide, potassium carbonate, cesium carbonate, potassium phosphate or any other suitable base. In one embodiment, the solvent used for the conversion of Compound 10 into Compound 5 is DMF. In other embodiments, the solvent employed for the conversion of Compound 10 into Compound 5 is THF, acetonitrile, DCM, DCB, ethanol, methanol, dioxane, NMP or any other suitable solvent.

Compound 5 is converted into a compound of Formula (II) in the presence of any suitable base and an acetate ester of Formula (IV) comprising an outlet group. In one embodiment, the reaction of Compound 5 with

methyl bromoacetate or methyl chloroacetate provides a compound of Formula

(II) in which R is methyl (Compound 2). In a different embodiment, the reaction of Compound 5 is carried out

image92

cijl

with ethyl bromoacetate or ethyl chloroacetate to provide a compound of

Formula (II) in which R is ethyl (Compound 2-A). Any suitable solvent is used. In one embodiment, the solvent is DMF. In alternative embodiments, the solvent is dioxane, acetonitrile, chloroform, dichloromethane, tetrahydrofuran (THF), N-methylpyrrolidone (NMP), dimethylsulfoxide (DMSO) and the like. In one embodiment, a compound of Formula (II) is aflaid as a wet cake which is optionally washed with ethyl acetate and isopropanol and / or a combination thereof, cooled.

Synthesis of Compounds of Formula (I) from compounds of Formula (II) Scheme 6a describes an exemplary synthesis of Compounds of Formula (I).

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Scheme 6a

image93

A method of synthesizing Compound 1 is provided herein in some embodiments. The synthesis of Compounds of Formula (II) has been described above (eg, Schemes 1, 4 and 5). In some embodiments, a compound of Formula (II) is transformed into Compound 1. In some embodiments, a compound of Formula (II) is transformed into a compound of Formula (III). In some embodiments, a compound of Formula (III) is transformed into a compound of Formula (I-A). In complementary or additional embodiments, a compound of Formula (I-A) is transformed into Compound 1.

In some embodiments, a compound of Formula (II) is joking in the presence of a joking agent to provide a compound of Formula (III). In some embodiments, the bromination of a compound of Formula (II) in which R = H provides Compound 1. In certain embodiments, the brominating agent is N-bromosuccinimide (NBS), Br2, BrCl / Br2, tetrabutylammonium tribromide , ammonium bromide / oxone (in methanol and / or water), selenium dibromide, FeBr3 / Br2, AlCl3 / Br2, FeCh / Br2, ZnCh / Br2, 1,2-dipyridinium ethane tribromide, NBS / acid (trifluoromethanesulfonic acid and BF3-H2O), NBS / concentrated sulfuric acid, NBS / tetrabutylammonium bromide, LiBr / PhI / m-chloroperbenzoic acid / TsOH, AuCL / NBS, NBS / Pd (OAc) 2, N, N, N ', N' -tetrabromobenzene-1,3-

disulfonylamide / poly [N-bromobenzene-1,3-disulfonylamide], LiTMP / ZnCl2 / Br2, [Ir (COD) (oMe)] 2 / B2pin2 / dtbpy / CuBr2 or [Ir (COD) (OMe)] 2 / B2pin2 / dtbpy / CuCl2. Any suitable solvent for joking can be used. In some embodiments, the solvent is water, acetonitrile, DMF, THF, toluene, xylenes, dioxane, butanol, methanol, ethanol, diethyl ether, acetone, hexane, pentane, heptane, ethyl acetate, dichloromethane, dichloroethane, dichlorobenzene, NMP or combinations thereof.

In some embodiments, a compound of Formula (III) is optionally hydrolyzed in the presence of a base to provide a compound of Formula (I-A) in which M is a cation. In certain embodiments, M is selected from Na +, Li +, K +, Cs +, Ba +, Ca + or any other suitable cation. In some embodiments, the base is sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, barium hydroxide, ferrous hydroxide, calcium hydroxide, ammonia or any other suitable base. In certain embodiments, it is potassium bicarbonate, potassium carbonate, potassium acetate, potassium hydroxide, sodium acetate, sodium benzoate, sodium bicarbonate, sodium carbonate, sodium hydroxide, sodium metasilicate, sodium sesquicarbonate, trisodium phosphate, calcium carbonate, calcium hydroxide, cesium or potassium phosphate. Any suitable solvent for joking can be used. In some embodiments, the solvent is water, acetonitrile, DMF, THF, toluene, xylenes, dioxane, butanol, methanol, ethanol, diethyl ether, acetone, hexane, pentane, heptane, ethyl acetate, dichloromethane, dichloroethane, dichlorobenzene, NMP or combinations thereof. In some embodiments, the solvent is water.

In some embodiments, a compound of Formula (IA) is optionally treated with an acid to provide Compound 1. In some embodiments, the acid is bromhydric acid, sulfuric acid, hydrochloric acid, hydroiodic acid, nitric acid, phosphoric acid, fluoroantimonic acid , fluoroboric acid, hexafluorophosphoric acid, trifluoroacetic acid, acetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, cfric acid, formic acid, gluconic acid, maleic acid, oxic acid , tartaric acid or any suitable acid. Any suitable solvent can be used to provide the free acid Compound 1. In some embodiments, the solvent is water, acetonitrile, DMF, THF, toluene, xylenes, dioxane, butanol, methanol, ethanol, diethyl ether, acetone, hexane, pentane, heptane, ethyl acetate, dichloromethane, dichloroethane, dichlorobenzene, NMP or combinations thereof. In some embodiments, the solvent is ethyl acetate and heptane.

In some embodiments of the process discussed above (Scheme 6a), the compounds (eg, compounds of Formula (III), (I-A) and Compound 1) are relaxed and used in subsequent synthetic steps without further purification steps. In certain embodiments, the compounds (eg, compounds of Formula (III), (I-A) and Compound 1) are used without intermediate isolation or purification steps. In some embodiments, the compounds (eg, compounds of Formula (III), (I-A) and Compound 1) are purified before being used in additional synthetic steps. In certain embodiments, the compounds (eg, compounds of Formula (III), (I-A) and Compound 1) are purified by crystallization. In some embodiments, the compounds (eg, compounds of Formula (III), (IA) and Compound 1) are purified by distillation, column chromatography, reverse phase chromatography, preparative thin layer chromatography or combinations thereof .

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Scheme 6b describes an exemplary synthesis of Compounds of Formula (I), including Compound 1 and Compound 4.

Scheme 6b

image94

Reaction of a compound of Formula (II) with N-bromosuccinimide (NBS) in a suitable solvent provides a compound of Formula (III). Suitable solvents for the NBS-mediated reaction include DMF, acetonitrile, MTBE or any other suitable solvent. The ester group in a compound of Formula (III) is optionally hydrolyzed to provide an acid salt of a compound of Formula (I), that is, a compound of Formula (IA) in which M is selected from Na +, Li +, K +, Cs + or any other suitable cation. The acid salt is optionally isolated and / or crystallized. The compound of Formula (I-A) is converted to Compound 1 in the presence of an acid. Compound 1 is optionally crystallized from a suitable solvent or mixture of solvents.

In a specific embodiment, Scheme 7 describes the synthesis of Compound 1 and Compound 4.

Scheme 7

image95

Accordingly, a procedure (Procedure 8) for preparing Compound 1 having the following structure is provided herein:

image96

the improvement in the process being to contact a structure compound

image97

with a brominating agent (eg, N-bromosuccinimide (NBS)) and a solvent.

In one embodiment, the solvent is THF. In alternative embodiments, the solvent is DMF, acetonitrile or any other suitable solvent.

In one case, the NBS is added to a solution of Compound 2 in THF while the THF solution is maintained at a temperature between about room temperature and about 32 ° C. In one embodiment, the reaction mixture is then stirred for at least 12 hours at a temperature between about room temperature and about 32 ° C. In alternative embodiments, the reaction mixture is stirred for at least 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 20 hours, 24 hours or more. In one case, if the content of Compound 2 in the reaction mixture test is> 1.5% of the area by high performance liquid chromatography (HPLC), an additional amount of NBS is added to the reaction mixture. In one embodiment, after stirring the reaction mixture for at least 12 hours, and / or optionally adding an additional amount of NBS, the reaction mixture test shows <1.5% of area 10 by HPLC of Compound 2. In another embodiment, after stirring the reaction mixture for at least 12 hours and / or optionally adding an additional amount of NBS, the reaction mixture test shows <0.2% of the HPLC area of Compound 2.

In one embodiment, a method for the synthesis of Compound 1 further comprises

15 (1-i) extract the reaction mixture with a solvent (e.g., toluene) while the mixture is kept at a

temperature between about 2 ° C and about 7 ° C;

(1-ii) re-extract the organic phase from step (1-i) with a solution of sodium disulfite one or more times until the NBS is undetectable in the aqueous phase by HPLC testing;

(1-iii) wash the organic phase from stage (1-ii) with water,

20 (1-iv) wash the organic phase from step (1-iii) with a solution of sodium bicarbonate one or more times

until the aqueous phase has a pH of at least 8; Y

(1-v) collect the organic phase comprising a compound of structure:

image98

In one case, the process further comprises optionally concentrating the organic phase of step (1-v) under reduced pressure to obtain Compound 3.

In one case, the procedure also includes the steps of

(1-vi) contacting the organic phase in step (1-v) of claim 7 with a solution of a base (eg, sodium hydroxide) until the peak area of Compound 3 in the phase Organic is less than 50 mAU by the HPLC assay; Y

(1-vii) collect the aqueous phase comprising a compound of structure:

image99

In one case, the procedure also includes the steps of

(1-viii) concentrate the aqueous phase in step (1-vii) of claim 8 under reduced pressure;

(1-ix) add water to adjust the volume of the mixture in step (1-viii) to approximately 5.5 ± 5% the weight calculated in the HPLC test of Compound 1 in the aqueous phase of stage (1 -viii);

(1-x) cooling the mixture of step (1-ix) to obtain a suspension comprising crystalline Compound 4; Y

5 (1-xi) filter the suspension of step (1-x) to obtain a wet cake comprising crystalline Compound 4.

In one case, the process further comprises optionally drying the wet cake of step (1-xi) to obtain Compound 4.

In one case, the process further comprises the steps of 10 (1-xii) dissolving the wet cake comprising Compound 4 of step (1-xi) of claim 10 in water;

(1-xiii) add a solvent (eg ethyl acetate) to the solution of step (1-xii);

(1-xiv) add an acid (e.g., 24% hydrochloric acid) while maintaining the temperature of the reaction mixture below 35 ° C, and maintaining the pH of the reaction mixture between approximately 2 , 0 and about 4.0; Y

15 (1-xv) separate the organic phase comprising Compound 1.

In one case, the procedure also includes

(1-xvi) concentrate the organic phase of step (1-xv) of claim 10 under reduced pressure;

(1-xvii) stir the mixture of step (1-xvi) between about 32 ° C and about 38 ° C for at least 8 hours;

20 (1-xviii) add a cosolvent (eg, n-heptane) to the mixture of step (1-xvii) and cool the mixture; and (1-xix) filter the suspension of step (1-xviii) to obtain Compound 1.

In one embodiment, step (1-xix) above gives Crystalline Compound 1. Crystalline polymorphs of Compound 1 are described in PCT International Application No. PCT / US11 / 20233 and International PCT Application No. PCT / US11 / 67657 and the disclosure of polymorphs of Compound 1 and / or Compound 4 described in Application 25 International PCT No. PCT / US 11/20233 and International Application pCT No. PCT / US11 / 67657 is incorporated herein by reference.

Compound 1, which has no more than 0.1% of Compound 3 in the area in an HPLC assay, is described herein. In one case, Compound 1 having no more than 0.1% of Compound 3 is obtained by the 30 procedures described above. Compound 1, which has no more than 0.1% of Compound 2, and not more than 0.1% of Compound 3 in the area in an HPLC assay is also described herein. Also described herein is Compound 1 having a purity of> 98%. Compound 1 having a purity of> 99% is also described herein. In any of the above cases, purity is determined by an HPLC assay. In any of the above cases, Compound 1 is prepared by means of Procedure 1, Procedure 2, Procedure 3, Procedure 4, Procedure 5, Procedure 6, Procedure 7 or Procedure 8 or any combination of the same.

Additional forms of Compounds of the compounds described herein

Isomers

In some cases, the compounds described herein exist as geometric isomers. In some cases, the compounds described herein possess one or more double bonds. The compounds presented here include all cis, trans, sin, anti, entgegen (E) and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. In

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In some situations, the compounds described herein have one or more chiral centers and each center exists in the R or S configuration. The compounds described herein include all diastereoisomere, enantiomeric and epfomeric forms as well as the corresponding mixtures of the same. In additional cases of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers, which result from a single preparative stage, combination or interconversion, are useful for the applications described herein. In some cases, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereisomers and recovering the optically pure enantiomers. In some cases, dissociable complexes are preferred (eg, crystalline diastereoisomeric salts). In some cases, diastereisomers have different physical properties (eg, melting points, boiling points, solubilities, reactivity, etc.) and are separated taking advantage of these differences. In some cases, diastereisomers are separated by chiral chromatography or, preferably, by separation / resolution techniques based on differences in solubility. In some cases, the optically pure enantiomer is recovered, together with a resolution agent, by any practical means that does not result in racemization.

Marked Compounds

In some cases, the compounds described herein exist in their isotopically labeled forms. In some cases, the methods disclosed herein include methods for treating diseases by administering such isotopically labeled compounds. In some cases, the methods disclosed herein include methods for treating diseases by administering such isotopically labeled compounds as pharmaceutical compositions. Thus, in some cases, the compounds described herein include isotopically labeled compounds, which are identical to those cited herein, except for the fact that one or more atoms are replaced by an atom having an atomic mass or a number of mass different from the atomic mass or the number of mass usually found in nature. Examples of isotopes that can be incorporated into the compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P , 32P, 35S, 18F and 36Cl, respectively. The compounds, and metabolites, pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates or derivatives thereof containing the aforementioned isotopes and / or other isotopes of other atoms are described herein. Certain isotopically labeled compounds, for example those in which radioactive isotopes such as 3H and 14C are incorporated, are useful in tissue distribution assays of drugs and / or substrates Tritiated isotopes, i.e. 3H and carbon 14, that is, 14C, are particularly preferred for their ease of preparation and detection capability. In addition, substitution with heavy isotopes such as deuterium, that is, 2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example, increase in half-life in vivo or reduction in dosage requirements. In some cases, the compounds, the pharmaceutically acceptable salt, the ester, the prodrug, the solvate, the hydrate or the derivative thereof, isotopically labeled, are prepared by any suitable method.

In some cases, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophors or fluorescent moieties, bioluminescent markers or chemiluminescent markers.

Pharmaceutically acceptable salts

In some cases, the compounds described herein exist as their pharmaceutically acceptable salts. In some cases, the methods disclosed herein include methods for treating diseases by administering such pharmaceutically acceptable salts. In some cases, the methods disclosed herein include methods for treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

In some cases, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some cases, these salts are prepared in situ during the final isolation and purification of the compounds described herein or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed. .

Examples of pharmaceutically acceptable salts include salts prepared by reacting the compounds described herein with an organic mineral acid or an inorganic base, including such salts acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexino-1,6-dioate, hydroxybenzoate, Y-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide,

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40

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isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, p-3, p-3-phosphate propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulphite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undeconate and xylenesulfonate.

In addition, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, acid. bromhydric, sulfuric acid, metric acid, phosphoric acid, metaphosphoric acid and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succmic acid, malic acid, maleic acid, smoking acid, Q-toluenesulfonic acid, tartaric acid, tartaric acid trifluoroacetic acid, dric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, 2-hydroxyethanesulfonic acid -naphthalenesulfonic acid, 4-methylbicyclo acid [2,2.2] oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4-methylenebis- (3-hydroxy-2-ene-1-carboxylic acid) , 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salidic acid, stearic acid and muconic acid. In some cases, other acids, such as oxalic, although not pharmaceutically acceptable themselves, are used in the preparation of useful salts as intermediates to obtain the compounds described herein and their salts by the addition of pharmaceutically acceptable acid.

In some cases, the compounds described herein comprising a free acid group react with a suitable base, such as hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia or with a primary, secondary or amine amine. pharmaceutically acceptable organic tertiary. Representative alkaline or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C-m alkyl) 4 and the like.

Representative organic amines useful for the formation of salts by base addition include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quaternization of any groups containing basic nitrogen containing. In some cases, products soluble or dispersible in water or oil are obtained by means of such quaternization. The compounds described herein can be prepared as pharmaceutically acceptable salts formed when an acid proton present in the original compound is well replaced by a metal ion, for example an alkali metal ion, an alkaline earth ion or an aluminum ion; or it is coordinated with an organic base. Base addition salts can also be prepared by reacting the free acid form of the compounds described herein with an inorganic or organic base pharmaceutically acceptable, including, but not limited to organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like and inorganic bases such as aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide and the like. In addition, the salt forms of the disclosed compounds can be prepared using salts of the raw materials or intermediates.

Solvates

In some cases, the compounds described herein exist as solvates. Methods for treating diseases when administering such solvates are described. Methods for treating diseases by administering such solvates as pharmaceutical compositions are also described.

Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some cases, are formed during the crystallization process with pharmaceutically acceptable solvents such as water, ethanol and the like. Hydrates are formed when the solvent is water or alcoholates are formed when the solvent is an alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the procedures described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared by recrystallization from a mixture of aqueous / organic solvents, using organic solvents that include, but are not limited to, dioxane, tetrahydrofuran or methanol. In addition, the compounds provided herein may exist in non-solvated as well as solvated forms. In general, solvated forms are considered equivalent to non-solvated forms for the purposes of the compounds and the methods provided herein.

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Polymorphs

In some cases, the compounds described herein exist as polymorphs. Methods for treating diseases by administering such polymorphs are described. Methods for treating diseases by administering such polymorphs as pharmaceutical compositions are also described.

Thus, the compounds described herein include all their crystalline forms, known as polymorphs. Polymorphs include different forms of crystalline packaging of the same elementary composition of a compound. In certain cases, polymorphs have different patterns of X-ray diffraction, infrared spectra, melting points, density, hardness, crystalline conformation, optical and electrical properties, stability and solubility. In certain cases, various factors such as the recrystallization solvent, crystallization rate and storage temperature cause a single crystalline form to dominate.

Polymorph form 1

In one case, the polymorphic form 1 of 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthium) acetate exhibits a ray diffraction pattern X of the powder characterized by the diffraction pattern summarized in Table 1A or Table 1B. In some cases, a 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H- 1,2,4-triazol-3-ylthio) acetate polymorph is described herein comprising at least 3 peaks of (± 0.1 ° 29) of Table 1A or 1B. In certain cases, a 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthio) acetate polymorph is described herein comprising at least 4 peaks of (± 0.1 ° 29) of Table 1A or 1B, at least 5 peaks of (± 0.1 ° 29) of Table 1A or 1B, at least 6 peaks of (± 0.1 ° 29 ) of Table 1A or 1B, at least 8 peaks of (± 0.1 ° 29) of Table 1A or 1B, at least 10 peaks of (± 0.1 ° 29) of Table 1A, at least 15 peaks of (± 0.1 ° 29) of Table 1A, at least 20 peaks of (± 0.1 ° 29) of Table 1A, at least 25 peaks of (± 0.1 ° 29) of Table 1A or at least 30 peaks of (± 0.1 ° 29) of Table 1A.

TABLE 1A

 form 1

 ° 29

 space d (A) Intensity (%)

 10.32

 8,562 100

 18.84

 4,706 32.7

 20.75

 4,277 23.2

 27.28

 3,266 13.6

 27.60

 3,229 11

 21.54

 4,123 10.4

 25.53

 3,487 9.8

 6.80

 12,989 9.4

 24.97

 3,563 9.1

 28.43

 3,137 8.4

 19.98

 4,441 6.9

 29.35

 3,040 6.7

 15.88

 5,577 5.4

 23.13

 3,842 4.8

 26.34

 3,381 4.8

 18.56

 4,777 4.1

TABLE 1B

 form 1

 ° 29

 space d (A) Intensity (%)

 10.32

 8,562 100

 18.84

 4,706 32.7

 20.75

 4,277 23.2

 27.28

 3,266 13.6

In a case described herein, the polymorphic form 1 of 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-5 3-ylthio) acetate is characterized by spikes of the X-ray powder diffraction pattern at 10.32, 18.84 and 20.75 ° 20 ± 0.1 ° 29. In additional cases, polymorphic form 1 is further characterized by at least one peak that appears at 6.80, 21.54, 24.97, 25.53, 27.28 and 27.60 ° 29 ± 0.1 ° 29 . In additional cases, polymorphic form 1 is further characterized by at least two peaks that appear at 6.80, 21.54, 24.97, 25.53, 27.28 and 27.60 ° 29 ± 0.1 ° 29 . In further additional cases, the polymorph exhibits a powder X-ray diffraction pattern substantially equal to the powder X-ray diffraction pattern shown in FIGURE 1.

Polymorph Form 2

In one case, the polymorphic form 2 of 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthium) acetate exhibits a ray diffraction pattern X of the powder characterized by the diffraction pattern summarized in Table 2A or Table 2B. In some cases, a 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H- 15 1,2,4-triazol-3-ylthio) acetate polymorph comprising the minus 3 peaks of (± 0.1 ° 29) of Table 2A or 2B. In certain cases, a 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthio) acetate polymorph is described herein comprising at least 4 peaks of (± 0.1 ° 29) of Table 2A or 2B, at least 5 peaks of (± 0.1 ° 29) of Table 2A or 2B, at least 6 peaks of (± 0.1 ° 29 ) of Table 2A or 2B, at least 8 peaks of (± 0.1 ° 29) of Table 2A or 2B, at least 10 peaks of (± 0.1 ° 29) of Table 2A, at least 15 peaks of (± 0.1 ° 29) of Table 2A, at least 20 peaks of (± 0.1 ° 29) of 20 Table 2a, at least 25 peaks of (± 0.1 ° 29) of Table 2A or at least 30 peaks of (± 0.1 ° 29) of Table 2A.

TABLE 2A

 form 2 Observed

 ° 29

 space d (A) Intensity (%)

 7.97

 11,086 13.8

 9.66

 9,148 26.1

 10.46

 8,449 83.8

 11.96

 7,394 41.3

 12.55

 7,046 16.7

 12.94

 6,836 15.7

 13.82

 6,402 41.6

 16.19

 5,471 49.8

 18.21

 4,867 74.0

 18.76

 4,727 81.4

 19.02

 4,662 35.6

 19.51

 4,548 15.9

 19.83

 4,474 100.0

 20.40

 4,349 13.4

 21.36

 4,157 12.3

 22.50

 3,948 36.7

 22.88

 3,884 30.6

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 form 2 Observed

 ° 29

 space d (A) Intensity (%)

 23.08

 3,850 56.1

 24.01

 3,704 42.1

 25.15

 3,539 35.2

 25.46

 3,496 20.5

 26.06

 3,417 13.4

 26.51

 3,360 35.7

 27.97

 3,187 26.8

 29.93

 2,983 37.0

 30.42

 2,936 12.4

 31.77

 2,814 17.1

 32.35

 2,765 38.2

 34.26

 2,615 12.8

 38.01

 2,366 16.5

 38.88

 2,314 10.0

TABLE 2B

 representative form 2

 ° 29

 space d (A) Intensity (%)

 18.83

 4,474 100.0

 10.46

 8,449 83.8

 18.76

 4,727 81.4

 18.21

 4,867 74.0

 23.08

 3,850 56.1

In a case described herein, the polymorphic form 2 of 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthio) acetate is characterized by X-ray powder diffraction pattern peaks at 10.46, 18.76 and 19.83 ° 29 ± 0.1 ° 29. In additional cases, polymorphic form 2 is further characterized by at least one peak that appears at 18.21 or 23.08 ° 29 ± 0.1 ° 29. In additional cases, the polymorphic form 2 is further characterized by two peaks that appear at 18.21 or 23.08 ° 29 ± 0.1 ° 29. In other additional cases, the polymorphic form 2 exhibits a powder X-ray diffraction pattern substantially the same as the powder X-ray diffraction pattern shown in FIGURE 5.

In certain cases, crystalline polymorphs of 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthio) acetate were found to exhibit increased stability in comparison with the amorphous solid form of carboxylic acid. In some cases, the improved stability of the crystalline polymorphs of 2- (5-bromo-4- (4- cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthium) acetate provides the preparation of Pharmaceutical dosage forms that exhibit reduced variability in the dosage present in a given dosage form, reduction in the presence of impurities in the final pharmaceutical product and an improved duration of the dosage form formulated when compared with the pharmaceutical dosage form prepared with the solid amorphous form of carboxylic acid. In some cases, a polymorph described herein (e.g., Form 1 or Form 2) shows no degradation (e.g., less than 0.01%, less than 0.1%, less than 0 , 5% by weight.) For at least 3 months under accelerated conditions (e.g., 40 ° C-75% RH), for at least 4 months under accelerated conditions (e.g., 40 ° C-75 RH%), for at least 5 months under accelerated conditions (e.g., 40 ° C-75% RH), for at least 6 months under accelerated conditions (e.g., 40 ° C-75% of RH), for at least 9 months under accelerated conditions (e.g., 40 ° C-75% RH), for at least 12 months under accelerated conditions (e.g., 40 ° C-75% RH) and / or (ii) for at least 12 months under long-term conditions (e.g., 25 ° C- 60% RH), for at least 18 months under long-term conditions (e.g., 25 ° C-60% RH), for at least 24 months under long-term conditions (e.g., 25 ° C-60% RH).

Additionally, in certain cases, crystalline polymorphs of 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthium) acetate were found to exhibit a decrease of hygroscopicity compared to other forms in solid state as determined by gravimetric studies of vapor sorption (GVS). FIGURE 12 illustrates a study of GVS of form 1 and form 2. It was found that form 1 adsorbed <0.2% w / w with high humidity 5 and it was found that form 2 adsorbed <0.1% p / p with high humidity. This property of decreased hygroscopicity helps a lot in the preparation of solid pharmaceutical dosage forms.

Polymorph form A

In one case, the polymorphic A form of 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-yl) sodium acetate exhibits a diffraction pattern of X-rays of the powder characterized by the diffraction pattern summarized in Table 10 1A or Table 1B. In some cases, a sodium 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthio) acetate polymorph comprising the minus 3 peaks of (± 0.1 ° 29) of Table 1A or 1B. In certain cases, a polymorph of 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-yl) sodium acetate comprising the minus 4 peaks of (± 0.1 ° 29) of Table 1A or 1B, at least 5 peaks of (± 0.1 ° 29) of Table 1A or 1B, at least 6 peaks of (± 0.1 ° 29) of Table 1A or 1B, at least 8 peaks of (± 0.1 ° 29) of 15 Table 1A or 1B, at least 10 peaks of (± 0.1 ° 29) of Table 1A, at least 15 peaks of (± 0.1 ° 29) of Table 1A, at least 20 peaks of (± 0.1 ° 29) of Table 1A, at least 25 peaks of (± 0.1 ° 29) of the Table 1A or at least 30 peaks of (± 0.1 ° 29) of Table 1A.

Claims (11)

5 10 fifteen twenty 25 30 35 1. A procedure to prepare a compound of Formula (III): image 1 which comprises contacting a compound of Formula (II): image2 wherein R is -C1-C20 alkyl, -C1-C20 alkenyl, -C3-C10-cycloalkyl or -C3-C10-cycloalkenyl; with N-bromosuccinimide (NBS) and a solvent. 2. The method according to claim 1, wherein R is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, isoamyl, pentyl, hexyl, heptyl, octyl, nonyl, terpenyl, bornyl, allyl, linalyl or geranyl; or R is methyl or ethyl. 3. The method according to any one of claims 1-2, wherein the compound of Formula (II), the NBS and the solvent are stirred: for at least 12 hours; Y at a temperature between room temperature and 32 ° C. 4. The method according to any one of claims 1-3, further comprising contacting the compound of Formula (III) with a solution of sodium hydroxide to provide Compound 4: image3 5. The process according to claim 4, which comprises crystallizing Compound 4 in the aqueous sodium hydroxide solution. 6. The method according to claim 4, further comprising contacting Compound 4 with an acid to provide Compound 1: 5 10 fifteen twenty 25 image4 and optionally in which the acid is hydrobromic acid. 7. The method according to claim 4, further comprising (a) dissolve Compound 4 in water and add ethyl acetate to the mixture; Y (b) contacting the biphasic mixture of step (a) with an acid and separating the organic phase to provide Compound 1. 8. A reaction mixture comprising a compound of Formula (II): image5 wherein R is -C1-C20 alkyl, -C1-C20 alkenyl, -C3-C10-cycloalkyl or -C3-C10-cycloalkenyl; a joking agent; and a solvent; and optionally where the brominating agent is N-bromosuccinimide (NBS). 9. The method according to claim 1, wherein a compound of Formula (II) is prepared by a method comprising: contact compound 5: image6 (Compound 5); with: one base; a solvent; Y a compound of Formula (IV): ; - VR Formula (IV); 5 in which X is halo, tosylate, mesylate, triflate or besylate; Y R is -C1-C20 alkyl, -C1-C20 alkenyl, -C3-C10-cycloalkyl or -C3-C10 -cycloalkenyl and optionally (i) wherein the compound of Formula (IV) is selected from methyl bromoacetate, ethyl bromoacetate, methyl chloroacetate and ethyl chloroacetate; or 10 (ii) wherein a crude reaction product comprising a compound of Formula (II) is washed with a cooled mixture of ethyl acetate and isopropanol. 10. Compound 2 0 Compound 2-A: image7 15 11. A reaction mixture comprising Compound 5: image8 a compound of Formula (IV): (Compound 5); Formula (IV); in which: X is an output group; and R is -C1-C20 alkyl, -C1-C20 alkenyl, -C3-C10-cycloalkyl or -C3-C10 -cycloalkenyl; 5 10 fifteen twenty 25 one base; and a solvent; and optionally wherein the compound of Formula (IV) is methyl bromoacetate, ethyl bromoacetate, methyl chloroacetate or ethyl chloroacetate. 12. The method according to claim 9, wherein Compound 5 is prepared by a method comprising: (5-i) contact Compound 6: image9 (Compound 6); with metric acid, water and a solvent to provide compound 7: image10 (Compound 7) (5-ii) contacting Compound 7 with hydrogen, palladium on charcoal and one or more solvents to provide Compound 8: image11 (Compound 8); (5-iii) contacting Compound 8 with an acid to provide a salt of Compound 8; (5-iv) contacting the salt of Compound 8 of step (5-iii) with a base, thiophosgene and a solvent to provide Compound 9: image12 (Compound 9); (5-v) contacting Compound 9 with formylhydrazine and a solvent to provide Compound 10: image13 (Compound 10); Y 5 (5-vi) contacting Compound 10 with a base, water and a solvent to provide Compound 5: image14 (Compound 5). image15 image16 00 cn image17 FIGURE3 image18 0.02561% Weight Change at 130 ° C (0.001818 mg) 90 20 40 60 80 100 120 140 160 180 200 Temperature ° C 100 0.03758% Weight Change at 130 ° C (0.002684 mg) 40 60 80 100 120 140 160 180 200 Temperature ° C image19 image20 FIGURE 6 image21 CD OR Thermal Flow (W / g) NJ O image22

 CD1

 • i

 3 "OR

 h- ^ i

 CD

 OR':

 Or:

 C"

 3rd

 J

FIGURE 8 image23 image24 image25 Weight Change (%) Weight Change (%) image26 Intensity (CPS) image27 8 * 29 (degrees) Thermal Flow (W / g) image28 Temperature (° C) Log 0 / R) image29 Intensity (counts) image30 Raman offset (1 / cm) Intensity (CPS) : ..... 30 '! ; image31 5! S ss 5S: SS 3 «f 35 <46 8 * 20 (degrees) Thermal Flow (W / g) image32 Intensity image33 8 * 29 (degrees) Thermal Flow (W / g) image34